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An efficient and practical protocol for the production of pretomanid (PA-824) via a novel synthetic strategy

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Abstract

An improved, practical and efficient protocol for the production of pretomanid (1) is described. Key to this optimization was the design and development of a novel synthetic strategy, which involves the preparation of key intermediate (S)-1-(tert-butyldimethylsilyloxy)-3-(2-chloro-4-nitro-1H-imidazol-1-yl) propan-2-ol (6) from 2-chloro-4-nitroimidazole (2) and (S)-epichlorohydrin (3) through nucleophilic substitution, hydrolysis and silicon etherification reactions, followed by further O-alkylation and intramolecular cyclization to obtain pretomanid with excellent quality and yield. The new route addressed the scalability issues that existed in the reported routes, in which the explosive 2,4-dinitroimidazole, expensive (S)-1-O-(tert-butyldimethylsilyl) glycidol and laborious workups can be avoided. Furthermore, this new synthetic route provides a more efficient method to pretomanid with the characteristics of cheap and easily available raw materials, mild experimental conditions, simple operation, ‘one-pot’ procedure, which is satisfied with the requirement of green chemistry and suitable for industrial production.

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Acknowledgements

This work was supported by Development Project of Ministry of Education Innovation Team (No. IRT1073) and Youth Backbone Talent Training Project of Shenyang Pharmaceutical University (No. ZQN2018008).

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Correspondence to Xin Zhai.

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Chen, G., Zhu, M., Chen, Y. et al. An efficient and practical protocol for the production of pretomanid (PA-824) via a novel synthetic strategy. Chem. Pap. 74, 3937–3945 (2020). https://doi.org/10.1007/s11696-020-01211-4

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  • DOI: https://doi.org/10.1007/s11696-020-01211-4

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